new england journal medicine

Transcription

new england
journal of medicine
The
established in 1812
october 31, 2013
vol. 369 no. 18
Autologous Transplantation as Consolidation
for Aggressive Non-Hodgkin’s Lymphoma
Patrick J. Stiff, M.D., Joseph M. Unger, Ph.D., James R. Cook, M.D., Ph.D., Louis S. Constine, M.D., Stephen Couban, M.D.,
Douglas A. Stewart, M.D., Thomas C. Shea, M.D., Pierluigi Porcu, M.D., Jane N. Winter, M.D., Brad S. Kahl, M.D.,
Thomas P. Miller, M.D., Raymond R. Tubbs, D.O., Deborah Marcellus, M.D., Jonathan W. Friedberg, M.D.,
Kevin P. Barton, M.D., Glenn M. Mills, M.D., Michael LeBlanc, Ph.D., Lisa M. Rimsza, M.D.,
Stephen J. Forman, M.D., and Richard I. Fisher, M.D.
A bs t r ac t
Background
The efficacy of autologous stem-cell transplantation during the first remission in
patients with diffuse, aggressive non-Hodgkin’s lymphoma classified as high-intermediate risk or high risk on the International Prognostic Index remains controversial and is untested in the rituximab era.
Methods
We treated 397 patients who had disease with an age-adjusted classification of high
risk or high-intermediate risk with five cycles of cyclophosphamide, doxorubicin,
vincristine, and prednisone (CHOP) or CHOP plus rituximab. Patients with a response
were randomly assigned to receive three additional cycles of induction chemotherapy (control group) or one additional cycle of induction chemotherapy followed
by autologous stem-cell transplantation (transplantation group). The primary efficacy end points were 2-year progression-free survival and overall survival.
Results
Of 370 induction-eligible patients, 253 were randomly assigned to the transplantation
group (125) or the control group (128). Forty-six patients in the transplantation group
and 68 in the control group had disease progression or died, with 2-year progressionfree survival rates of 69 and 55%, respectively (hazard ratio in the control group vs.
the transplantation group, 1.72; 95% confidence interval [CI], 1.18 to 2.51; P = 0.005).
Thirty-seven patients in the transplantation group and 47 in the control group died,
with 2-year overall survival rates of 74 and 71%, respectively (hazard ratio, 1.26;
95% CI, 0.82 to 1.94; P = 0.30). Exploratory analyses showed a differential treatment
effect according to risk level for both progression-free survival (P = 0.04 for interaction)
and overall survival (P = 0.01 for interaction). Among high-risk patients, the 2-year overall survival rate was 82% in the transplantation group and 64% in the control group.
Conclusions
From Loyola University Medical Center,
Maywood, IL (P.J.S., K.P.B.); Southwest
Oncology Group Statistical Center, Fred
Hutchinson Cancer Research Center, Seattle (J.M.U., M.L.); Cleveland Clinic, Cleveland (J.R.C., R.R.T.); University of Rochester, Rochester, NY (L.S.C., J.W.F., R.I.F.);
Queen Elizabeth II Health Sciences Centre and Dalhousie University, Halifax, NS
(S.C.), University of Calgary–Tom Baker
Cancer Centre, Calgary, AB (D.A.S.), and
Margaret and Charles Juravinski Cancer
Centre, Hamilton, ON (D.M.) — all in
Canada; University of North Carolina at
Chapel Hill, Chapel Hill (T.C.S.); Ohio
State University Medical Center, Columbus (P.P.); Northwestern University, Chicago (J.N.W.); University of Wisconsin,
Madison (B.S.K.); University of Arizona,
Tucson (T.P.M., L.M.R.); Louisiana State
University Health Sciences Center, Shreveport (G.M.M.); City of Hope Medical Center,
Duarte, CA (S.J.F.); and Fox Chase Cancer
Center–Temple Health, Temple University School of Medicine, Philadelphia
(R.I.F.). Address reprint requests to Dr.
Stiff at Loyola University Medical Center,
2160 S. First. Ave., Maywood, IL 60153.
This article was updated on October 31,
2013, at NEJM.org.
N Engl J Med 2013;369:1681-90.
DOI: 10.1056/NEJMoa1301077
Copyright © 2013 Massachusetts Medical Society.
Early autologous stem-cell transplantation improved progression-free survival
among patients with high-intermediate-risk or high-risk disease who had a response to induction therapy. Overall survival after transplantation was not improved, probably because of the effectiveness of salvage transplantation. (Funded
by the National Cancer Institute, Department of Health and Human Services, and
others; SWOG-9704 ClinicalTrials.gov number, NCT00004031.)
n engl j med 369;18 nejm.org october 31, 2013
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1681
The
A
n e w e ng l a n d j o u r na l
utologous stem-cell transplantation has long been known to improve
both progression-free survival and overall
survival among patients with diffuse, aggressive
non-Hodgkin’s lymphoma in second remission.1
When it became possible to identify patients at
diagnosis who have less than a 50% chance of
sustained remission, as defined by the International Prognostic Index2 (IPI) (see Table S1 in the
Supplementary Appendix, available with the full
text of this article at NEJM.org), trials of up-front
transplantation in this group were conducted. In
the first trial, LNH-87, patients received fullcourse induction chemotherapy, regardless of
their IPI risk category; those with a complete response were randomly assigned to transplantation or consolidation chemotherapy.3 Although a
survival advantage was not seen with transplantation, a retrospective subgroup analysis showed
improved progression-free survival and overall
survival among patients with high-intermediaterisk or high-risk disease.3
Results of phase 2 trials suggested a benefit
of consolidative transplantation in high-risk
groups4,5; however, few of the subsequent phase 3
trials showed a benefit.6-14 Numerous factors complicated interpretation of the results of these
trials, including insufficient sample size as a
result of high dropout rates, which were due to
early disease progression or a patient’s decision
to decline treatment, as well as trial designs that
differed from that of LNH-87. Thus, 15 years
after the first description of a potential benefit
of consolidative transplantation in high-risk disease, no role for this treatment has been clearly
established.
Given the limitations in comparing data from
previous trials because of differences in study
design, we evaluated the efficacy of autologous
stem-cell transplantation using a design similar
to that of LNH-87. Patients with high-intermediate-risk or high-risk disease who had a response
to five cycles of cyclophosphamide, doxorubicin,
vincristine, and prednisone (CHOP) induction
chemotherapy were randomly assigned either to
one additional cycle of induction chemotherapy
plus transplantation or to three additional cycles
of induction chemotherapy. Patients with early
disease progression and patients who elected not
to undergo transplantation did not proceed to the
randomization stage of the study, which minimized dropout. Patients in the control group
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who had a relapse were encouraged to undergo
salvage transplantation so that the efficacy of
early versus delayed transplantation strategies
could be evaluated.
After about one third of the patients had been
enrolled, it became clear that CHOP plus rituximab (R-CHOP) was superior to CHOP alone as
induction therapy for patients with CD20+ disease.15,16 Therefore, as of April 2003, R-CHOP
was used for this subgroup.
Me thods
Study Design, Patients, and Oversight
This randomized intergroup trial (Southwest Oncology Group [SWOG] trial 9704), conducted at
40 sites, was led by SWOG and included the Eastern Cooperative Oncology Group, Cancer and
Leukemia Group B, and the Canadian NCIC Clinical Trials Group. Eligible patients were 15 to 65
years of age and had biopsy-confirmed nonHodgkin’s lymphoma in Working Formulation
groups D through H and J, which includes follicular large-cell, diffuse small-cleaved-cell, diffuse
mixed small-cell and large-cell, diffuse large-cell,
large-cell immunoblastic, and small non–cleavedcell Burkitt’s and non-Burkitt’s lymphoma; lymphoblastic, transformed, and mantle-cell histologic
types were excluded. All patients were in an ageadjusted high-intermediate-risk or high-risk group
defined by the IPI. Central pathological review
was performed to determine eligibility, and a final diagnosis was issued on the basis of the 2008
World Health Organization criteria.17 A patient
could be enrolled at any time before the second
cycle of induction chemotherapy; patients with a
response were randomly assigned to a study group
after five cycles of induction. Enrollment began
on August 15, 1999, and concluded on December
15, 2007, when the enrollment goal was reached.
The trial was designed by the leadership of
the lymphoma committees of the U.S. and Canadian cooperative groups and was approved by the
National Cancer Institute. The data were gathered and analyzed by the SWOG Statistical Center and reviewed by all the authors. The first
draft of the manuscript was written exclusively
by the first author. All authors reviewed the
manuscript, made the decision to submit it for
publication, and vouch for the completeness and
accuracy of the data and analysis. No one who is
not listed as an author contributed to the writing
Autologous Tr ansplantation in Aggressive Lymphoma
of the manuscript. The complete protocol and its
amendments are available at NEJM.org. BristolMyers Squibb provided unrestricted capitation
payments to the enrolling sites to cover expenses associated with the trial for the study participants, but they had no role in data collection or
analysis or in manuscript preparation.
The study was performed in accordance with
the Declaration of Helsinki and Good Clinical
Practice guidelines and was approved by the local institutional review board at each participating site. Patients were required to provide written informed consent before enrollment.
397 Patients were included for initial
registration and assessed for eligibility
27 Were ineligible
13 Had incorrect histologic type
7 Had low or low-intermediate
IPI risk category
2 Were >65 yr of age
2 Had 2 courses of R-CHOP
before registration
1 Had incorrect disease stage
1 Had hepatitis B
1 Had breast cancer within
5 yr before registration
370 Were eligible
Treatment Plan
Stratification was performed on the basis of the
IPI risk category. Patients were treated with five
cycles of induction chemotherapy with CHOP or
R-CHOP administered every 3 weeks; patients
with at least a partial response after cycle 5 were
randomly assigned to receive either three additional cycles of induction chemotherapy (control
group) or a single cycle followed by autologous
stem-cell transplantation (transplantation group)
(Fig. S1 in the Supplementary Appendix). R-CHOP
was used in place of CHOP in patients with
CD20+ disease, starting in April 2003 (two thirds
of patients were enrolled after this date). Patients
assigned to transplantation underwent totalbody irradiation (12 Gy in eight 1.5-Gy fractions
twice daily on days −8 through −5) or received
high-dose carmustine (300 mg per square meter
of body-surface area) on day −6 with high-dose
etoposide (60 mg per kilogram of adjusted ideal
body weight) given on day −4 and high-dose cyclophosphamide (100 mg per kilogram of ideal
body weight) given on day −2.17 The decision to
use total-body irradiation was made by the site
investigators. All patients 60 years of age or older
received the carmustine-based regimen; all patients younger than 60 years of age at a given
institution either underwent total-body irradiation or received the carmustine-based regimen,
in accordance with institutional preference. Transplantation occurred on day 0; decisions about supportive care were made by the site investigators.
After completion of the study treatment, disease evaluation, consisting of physical examinations conducted at least quarterly and computed
tomographic scanning conducted quarterly, was
performed over a period of 2 years, beginning
on day 60. No additional therapy (including ad-
117 Were excluded from randomization
66 Had evidence of early disease
progression
23 Declined to participate
4 Were ineligible for randomization
8 Had toxic effects of treatment
5 Had incomplete institutional
testing for eligibility
4 Died before randomization
4 Declined because of problems
with insurance or transportation
3 Had unknown reasons
253 Underwent randomization
128 Were assigned to the
control group
125 Were assigned to the transplantation group
Figure 1. Registration of Patients and Randomization.
IPI denotes International Prognostic Index, and R-CHOP rituximab plus cyclo
phosphamide, doxorubicin, vincristine, and prednisone.
ditional radiotherapy) was permitted unless it
was for biopsy-confirmed residual or progressive
disease. Treatment responses were documented
as previously reported.18
Statistical Analysis
The objectives of the study were to compare progression-free survival and overall survival, within
a modified intention-to-treat design, among all
eligible patients who were randomly assigned to a
treatment group. The sample size was chosen under the assumption of a 2-year overall survival rate
of 60% in the control group; a hazard ratio of
1.5 corresponded to a 2-year survival rate of 71%
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The
Table 1. Characteristics of the 370 Patients Who Were Eligible
for Randomization at Diagnosis.*
Characteristic
Value
Age — yr
Median
51
Range
18.3–65.9
Male sex — no. (%)
218 (59)
B-cell lymphoma — no. (%)†
330 (89)
Diffuse large-B-cell lymphoma not otherwise specified
248 (67)
Primary mediastinal large-B-cell lymphoma
28 (8)
Unclassifiable, with features intermediate between diffuse
large-B-cell lymphoma and Burkitt’s lymphoma
28 (8)
Follicular lymphoma, grade 3
16 (4)
Burkitt’s lymphoma
Other
T-cell lymphoma — no. (%)†
5 (1)
5 (1)
40 (11)
Peripheral T-cell lymphoma not otherwise specified
20 (5)
Anaplastic large-cell lymphoma‡
13 (4)
Angioimmunoblastic T-cell lymphoma
7 (2)
of
m e dic i n e
5 years, with 2 years of additional follow-up,
would be required for a power of 0.82 to detect a
hazard ratio of 1.5 (control group vs. transplantation group), with the use of a log-rank test and
a one-sided alpha level of 0.05, assuming exponential survival distributions. We assumed that
25% of patients would not reach the randomization stage as a result of ineligibility, the patient’s
decision not to proceed to the randomization
stage of the study, or early disease progression;
thus, it was estimated that 360 patients would
need to be registered in order for 270 eligible
patients to be a ssigned to a treatment group.
Under the assumption of a 2-year progressionfree survival rate of 55% in the control group, a
hazard ratio of 1.5 corresponded to a 2-year progression-free survival rate of 67% in the transplantation group. All P values are based on twosided tests unless stated otherwise.
R E SULT S
Characteristics of the Patients
Disease stage — no. (%)
A total of 397 patients were registered (Fig. 1). Of
the 370 who were eligible for inclusion, 117 did
III
116 (31)
not proceed to the randomization stage of the
IV
232 (63)
study, in most cases because of early disease pro134 (36)
Performance status ≥2 — no. (%)§
gression (66 patients, 56%) or the patient’s deciElevated lactate dehydrogenase level — no. (%)
310 (84)
sion to decline randomization (23 patients, 20%).
Bone marrow involvement — no. (%)
83 (22)
Of the 253 patients randomly assigned to a treatment group, 128 were assigned to the control
Extranodal sites — no. (%)
group and 125 to the transplantation group.
0
126 (34)
The characteristics of the 370 eligible patients
1
149 (40)
are shown in Table 1. Forty-seven percent of
≥2
95 (26)
patients with B-cell non-Hodgkin’s lymphoma
B symptoms present — no. (%)
229 (62)
received R-CHOP as induction therapy. Once
International Prognostic Index risk category: high risk — no. (%)
118 (32)
rituximab was included, no patient who received
B-cell lymphoma treated with R-CHOP — no./total no.(%)
156/330 (47)
CHOP induction therapy for B-cell non-Hodgkin’s lymphoma received R-CHOP after random*R-CHOP denotes rituximab plus cyclophosphamide, doxorubicin, vincristine,
ization. There were no significant differences
and prednisone.
between the randomized groups with respect to
†The diagnosis was made on the basis of the World Health Organization classification.17
age, sex, risk group, initial stage, lactate dehy‡Patients who were positive or negative for anaplastic lymphoma kinase are
drogenase level, number of extranodal sites, or
included in this category. §Performance status was assessed according to the Eastern Cooperative Oncology B symptoms (i.e., weight loss, night sweats, and
Group scale, in which 0 indicates that the patient has no symptoms; 1, the pafever) (Table S2 in the Supplementary Appendix).
tient has symptoms but is ambulatory; 2, the patient is bedridden less than
The proportion of patients with B-cell nonhalf the day; 3, the patient is bedridden half the day or longer; and 4, the paHodgkin’s lymphoma who received R-CHOP as
tient is chronically bedridden and requires assistance with activities of daily
living.2
induction therapy was higher among patients
assigned to randomized treatment groups (60%)
in the transplantation group. We calculated that than among all registered patients (47%), india sample of 270 eligible patients randomly as- cating a higher dropout rate among those who
signed to a treatment group over a period of received CHOP induction therapy.
II, with bulky disease
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22 (6)
Toxic Effects
During the first five cycles of CHOP or R-CHOP,
there were four deaths; three were due to neutropenic infections, and one was due to hemorrhage. As expected, a markedly greater number
of grade 3 and grade 4 toxic effects was seen
among patients randomly assigned to transplantation (Table 2). In this group, six patients (5%)
died from toxic effects: three as a result of lung
damage, and one each as a result of hemorrhage
and renal failure, infection, and multiorgan failure. In the control group, three patients (2%)
died, one each as a result of cardiovascular toxic
effects, infection, and unknown factors.
Table 2. Grade 3 and 4 Toxic Effects of Treatment.
Toxic Effect
Transplantation
Group
(N = 125)
Control
Group
(N = 128)
percent of patients
Infection
50
13
Gastrointestinal effects
26
5
Metabolic effects
13
1
Lung effects
11
2
Cardiovascular effects
10
4
Neurologic effects
7
5
Dyspnea
7
2
Hyperglycemia
6
0
Outcomes
Hypoxia
4
0
After randomization, nine patients (7%) randomly
assigned to transplantation did not undergo the
procedure: six (5%) because they decided against
it and one each because of unsuccessful mobilization of stem cells, early disease progression,
and early death. Of the six patients who declined
transplantation, three did not have a relapse and
two had a relapse (one died from the relapse, and
one underwent salvage transplantation and survived); the sixth patient reversed the initial decision and underwent transplantation. In the control group, two patients (2%) received no further
chemotherapy, and one received rituximab monotherapy.
Forty-six of the 125 patients in the transplantation group and 68 of the 128 patients in the
control group had disease progression or died.
The estimated 2-year progression-free survival rate
was 69% in the transplantation group and 55%
in the control group (Fig. 2). In a multivariate Cox
regression model with adjustment for the risk
score, the hazard ratio for progression or death
in the control group versus the transplantation
group was 1.72 (95% confidence interval [CI],
1.18 to 2.51; P = 0.005; P = 0.002 in a one-sided
test). Median progression-free survival from initial registration was not reached in the transplantation group and was 2.8 years in the control group.
Thirty-seven of the 125 patients in the transplantation group and 47 of the 128 patients in
the control group died, at a median follow-up of
6.3 years. The estimated 2-year overall survival
rate was 74% in the transplantation group and 71%
in the control group (Fig. 2). In a multivariate Cox
regression with adjustment for the risk score, the
Hepatic effects
3
0
hazard ratio for death in the control group versus
the transplantation group was 1.26 (95% CI, 0.82
to 1.94; P = 0.30; P = 0.15 in a one-sided test).
Median overall survival from initial registration
was not reached for either group. The 9 patients
assigned to transplantation who did not undergo
the procedure had a 2-year progression-free survival rate of 56% (95% CI, 23 to 88) and an overall
survival rate of 78% (95% CI, 51 to 100). Results
for the main effect of treatment were similar
among all patients who underwent randomization, and there was no evidence that treatment
patterns differed according to receipt or nonreceipt of rituximab (data not shown).
In the control group, there were 11 second
cancers in 10 patients: skin cancer (4 cases),
breast cancer (2), follicular non-Hodgkin’s lymphoma (1), acute myeloid leukemia (1), prostate
cancer (1), multiple myeloma (1), and adenocarcinoma with unknown primary site (1). In the
transplantation group, there were 12 second cancers in 11 patients: skin cancer (3 cases), renal
cancer (3), thyroid cancer (2) myelodysplastic
syndrome (1), breast cancer (1), cervical cancer
(1), and lung cancer (1). Progression-free survival,
overall survival, second primary cancers, and
toxic effects of treatment were also analyzed according to the preparative regimen. In the comparison of preparative regimens, there was no
significant difference in progression-free survival or overall survival between patients receiving carmustine and patients receiving total-body
irradiation (P = 0.51 for progression-free survival
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The
A
Progression-free Survival (%)
100
90
P=0.005
80
70
Transplantation
60
50
40
No. of
2-Yr
No. at Relapses
Risk or Deaths Estimate
30
20
Transplantation group 125
128
Control group
10
0
0
3
46
68
Control
69%
55%
6
9
12
Years since Registration
B
100
Overall Survival (%)
90
P=0.30
80
Transplantation
70
60
50
Control
40
No. at
Risk
30
20
2-Yr
Estimate
37
47
74%
71%
Transplantation group 125
Control group
128
10
0
No. of
Deaths
0
3
6
9
12
Figure 2. Survival Rates among All Eligible Patients Who Underwent
Randomization.
Panel A shows rates of progression-free survival, and Panel B shows rates
of overall survival.
and P = 0.64 for overall survival). The incidence of
second cancers was also similar between patients
receiving carmustine and patients receiving total-body irradiation (11% and 5%, respectively),
as were the proportions of patients with grade 5
toxic effects (6% and 5%) and the proportions
with grade 4 or 5 toxic effects (81% and 80%).
Treatment Effect in Subgroups
Among the patients who underwent randomization, the IPI risk category distributions were similar among the 150 patients with B-cell lymphoma
treated with R-CHOP (36% were at high risk), the
75 patients with B-cell lymphoma treated with
CHOP (32% were at high risk), and the 28 patients
with T-cell lymphoma (36% were at high risk). No
differential treatment effect (i.e., statistical interaction) was noted between the subset of patients
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with B-cell lymphoma and the subset of patients
with T-cell lymphoma, for either progression-free
survival (P = 0.46) or overall survival (P = 0.56). In
the subgroup of patients with B-cell lymphoma,
the treatment effects on progression-free survival
and overall survival were similar to those in the
primary analysis; the hazard ratio for progression
or death was 1.84 (95% CI, 1.22 to 2.78; P = 0.004),
and the hazard ratio for death was 1.36 (95% CI,
0.85 to 2.20; P = 0.21). In this subgroup, the treatment effect also did not differ significantly between patients treated with R-CHOP and patients
treated with CHOP, for either progression-free survival (P = 0.33) or overall survival (P = 0.31). Among
patients with B-cell lymphoma who were treated
with R-CHOP, the estimated 2-year progressionfree survival rate was 73% in the transplantation
group and 63% in the control group (hazard ratio
for progression or death, 1.56; 95% CI, 0.92 to
2.63; P = 0.10; P = 0.05 in a one-sided test); the estimated 2-year overall survival rate was 77% in the
transplantation group and 73% in the control
group (hazard ratio for death, 1.09; 95% CI, 0.59 to
2.00; P = 0.79; P = 0.39 in a one-sided test).
The treatment effect did differ between highrisk patients and high-intermediate-risk patients
for both progression-free survival (P = 0.04 for
interaction) and overall survival (P = 0.01 for interaction). In the subset of 165 high-intermediaterisk patients, the 2-year progression-free survival
rate was 66% among patients in the transplantation group and 63% among patients in the control group (P = 0.32); in the subset of 88 high-risk
patients, the 2-year progression-free survival
rates were 75% and 41%, respectively (P = 0.001)
(Fig. 3). The estimated overall survival rates for
high-intermediate-risk patients in the transplantation and control groups were 70% and 75%,
respectively (P = 0.48), and those for high-risk
patients were 82% and 64% (P = 0.01). Subset
P values were unplanned, and no adjustments
were made for multiple comparisons. In the subset of patients with B-cell lymphoma, similar
patterns were observed for both progression-free
survival (P = 0.05 for interaction) and overall survival (P = 0.03 for interaction).
Treatment after Relapse
Of the 128 patients randomly assigned to the
control group, 62 (48%) had a relapse. Twentynine (47%) of these patients underwent salvage
chemotherapy and transplantation, 11 (38%) of
A Progression-free Survival among High-Intermediate-Risk Patients
B Progression-free Survival among High-Risk Patients
80
Transplantation (66% 2-yr survival)
70
60
50
Control (63% 2-yr survival)
40
30
20
10
0
100
P=0.32
90
100
0
3
6
9
80
70
60
50
40
30
20
10
0
12
P=0.001
90
0
3
C Overall Survival among High-Intermediate-Risk Patients
100
50
40
30
20
10
0
100
12
P=0.01
90
70
60
9
D Overall Survival among High-Risk Patients
P=0.48
90
80
6
80
70
60
50
40
30
20
10
0
3
6
9
12
0
0
3
6
9
12
Figure 3. Survival Rates among Eligible Patients Who Underwent Randomization, According to IPI Risk Category.
whom survived without disease progression. An
additional 7 patients survived without progression after alternative salvage therapy. In total, 18
(29%) of the 62 patients in the control group who
had a relapse survived without disease.
Of the 28 patients in the transplantation
group who had a relapse (median time to relapse,
6 months), 23 (82%) died, most after salvage
chemoimmunotherapy failed to induce a second
remission. Allogeneic stem-cell transplantation
was performed in 3 patients, 2 of whom died
from toxic effects, and 1 of whom had a subsequent relapse but was alive at the time of writing.
DISCUSSION
Numerous phase 3 trials of up-front autologous
stem-cell transplantation have not validated a
survival benefit in high-risk patients, but the
negative outcome in these trials was often influenced by the study design; patients were usually
randomly assigned to a treatment group at diagnosis, and approximately 15% did not receive the
assigned therapy because of early progression19
and as many as one third of those assigned to
transplantation declined it.6-14 Our study mirrored the LNH-87 trial design; as a result, the
dropout rate was greatly reduced, with only 5%
of patients assigned to the transplantation group
declining the procedure. Like many of the randomized trials and several meta-analyses,20,21
our study showed an improvement in progression-free survival for the combined high-risk and
high-intermediate-risk groups but no improvement in overall survival, probably because 29% of
patients who had a relapse or progression after
standard therapy had long-term progression-free
survival after salvage therapy that often included
transplantation. The outcomes were similar for
patients with T-cell disease and those with B-cell
disease, and among patients with B-cell disease,
the results were similar for those treated with
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The
R-CHOP and those treated with CHOP alone. In
addition, we saw no increase in the number of
late complications, including treatment-related
myeloid cancers, in patients who underwent transplantation, as compared with those in the control
group, probably because of the timing of transplantation in this study.
The difference in progression-free and overall
survival between the transplantation group and the
control group was especially pronounced among
patients in the high-risk subgroup. Although this
finding has some credibility because the patients
in the trial were stratified according to risk, this
analysis was not preplanned, and the study was
not powered to address this subgroup-related
question. Thus, the finding needs to be verified
prospectively, although undertaking such a trial
would be difficult, given the small fraction of
patients presenting with high-risk disease. However, the results of our analysis, as well as those
of phase 2 transplantation trials, in which the
4-year progression-free survival rates among patients with high-risk disease ranged from 64 to
78% after treatment with a rituximab-based induction regimen,22-27 compare favorably to the
50% progression-free survival rate after treatment
with R-CHOP alone,28 suggesting that early transplantation may be warranted in high-risk disease.
Advancements in the diagnosis and management of diffuse, aggressive non-Hodgkin’s lymphoma since the initiation of our study could make
transplantation decision-making more clear-cut.
Although it was not the standard of care during
trial enrollment, 18F-fluorodeoxyglucose with positron-emission tomography (FDG-PET) might have
been useful in identifying transplantation candidates after five cycles of CHOP or R-CHOP or an
even shorter induction regimen, because a positive scan does predict outcome when a regimen
of either duration is used.29-31 Treatment modifications have also been explored. Although pilot
studies suggested a benefit of dose-dense induction regimens, phase 3 trials have not shown
that they are superior to the standard 3-week
R-CHOP regimen.32-34 However, combining intensive, non-cross-resistant regimens as induction therapy in high-risk populations appears to
have promising results. Moskowitz and colleagues treated 98 patients with four cycles of
dose-dense R-CHOP followed by three cycles of
ifosfamide, carboplatin, and etoposide, reserving transplantation for the 5% of patients who
1688
of
m e dic i n e
had FDG-PET–positive and biopsy-positive disease after R-CHOP induction therapy.35 They reported a 79% progression-free survival rate among
their patients, 79% of whom were in the same
high-intermediate-risk and high-risk groups as
the patients in our study. It is notable that 7 of
the 12 patients with a relapse who did not initially undergo transplantation had a second
complete response after salvage transplantation,
which yielded a 90% overall survival rate.
Finally, although advances in defining adverse molecular abnormalities could, in theory,
be used to select patients for consolidative transplantation, it is unlikely that the overall outcomes
would improve for patients with these types of
lymphoma. In particular, adverse outcomes for
patients with “double-hit” lymphomas (tumors
with both MYC and BCL2 translocations) have
been described, with some studies suggesting
that transplantation be used for patients with a
treatment response.36,37 This subgroup of diffuse,
aggressive non-Hodgkin’s lymphoma accounts
for 3 to 5% of all B-cell non-Hodgkin’s lymphoma and is associated with high-risk clinical
features and central nervous system involvement.
Given the low incidence of this type of lymphoma and the frequent early failure of standard
therapy, typically before the timing of randomization in our trial, a transplantation benefit is
unlikely; in fact, data now suggest that autologous and even allogeneic transplants fail to improve the dismal prognosis for patients in this
subgroup.38 However, patients with intermediategrade non-Hodgkin’s (and non-Burkitt’s) lymphoma with MYC positivity alone also have an
adverse prognosis, as confirmed by a preliminary analysis of data from the current trial,39
and such patients may benefit from transplantation. Because the percentage of such patients is
small, however, prospective validation of transplantation in a randomized trial is unlikely.
In conclusion, although we found that progression-free survival was superior with early
transplantation among patients with high-intermediate-risk or high-risk non-Hodgkin’s lymphoma who had a response to induction therapy,
we could not validate a benefit of consolidative
transplantation with respect to overall survival,
probably because of the effectiveness of salvage
transplantation in the control group. Thus, early
transplantation and late transplantation achieve
roughly equivalent overall survival in the com-
bined risk groups. Early transplantation appears
to be beneficial for the small group of patients
presenting with high-risk disease.
Supported in part by Public Health Service Cooperative Agreement grants from the National Cancer Institute, Department of
Health and Human Services (CA32102, CA38926, CA11083,
CA46282, CA58658, CA13612, CA45377, CA35431, CA76448,
CA46441, CA35261, CA20319, CA22433, CA58416, CA46113,
CA63844, CA35090, CA63845, CA76447, CA04919, CA35178,
CA35281, CA14028, CA46368, CA67575, CA45560, CA58686,
CA52654, CA58861, CA35192, CA76132, CA37981, CA12644,
CA27057, CA077202, CA047559, CA077658, CA17145, CA21076,
and CA21115); by grants from the Canadian Cancer Society Research Institute (021039 and 015469); and in part by Bristol-Myers
Squibb.
Dr. Porcu reports receiving consulting fees from Hospira
and Medicis, lecture fees from Physician Education Resources,
honoraria from Easton Associates, ClearView Health Care
Partners, and E Squared Communications, and grant support
through his institution from Millennium. Dr. Kahl reports receiving payment for board membership from Roche, Seattle
Genetics, Millennium, and Cell Therapeutics and consulting
fees from Genentech and Celgene. Dr. Miller reports receiving
grant support through his institution from Spectrum, Celgene,
and Abbott. Dr. Tubbs reports receiving lecture fees from Ventana Medical Systems and grant support through his institution from Ventana Medical Systems and Abbott Molecular Vysis.
Dr. Friedberg reports receiving consulting fees from Genentech, Lilly, and Trubion. Dr. LeBlanc reports holding a pending
patent regarding the uses of diffuse large-B-cell lymphoma
markers. Dr. Rimsza reports receiving lecture fees from Ventana Medical Systems, and grant support through her institution from Ventana Medical Systems, Spectrum Pharmaceuticals,
and Merck. Dr. Fisher reports receiving consulting fees from
Micromet, Bio Linx, Boehringer Ingelheim, Roche, and Pfizer.
No other potential conflict of interest relevant to this article
was reported.
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
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Copyright © 2013 Massachusetts Medical Society.
clinical trial registration
The Journal requires investigators to register their clinical trials
in a public trials registry. The members of the International Committee
of Medical Journal Editors (ICMJE) will consider most reports of clinical
trials for publication only if the trials have been registered.
Current information on requirements and appropriate registries
is available at www.icmje.org/faq_clinical.html.
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